Abstract Due to rapid advances in RNA sequencing, scientists now have the ability to easily map transcriptome changes in cellular function and disease to complement a robust catalog of functional genome elements and variants. Genome editing tools, in particular the CRISPR-Cas9 platform, allow for rapid control and manipulation of genome sequences for genetic study. To extend these tools to the direct and facile perturbation of RNA, the proposed work aims to develop a broad suite of transcriptome engineering tools based on diverse RNA-targeting CRISPR systems to complement RNAi. Analogous to dCas9 for DNA, programmable RNA binding will enable modular modes of function including and beyond RNA knockdown, such as splice isoform engineering, by leveraging a combination of bioinformatic, biochemical, and protein engineering approaches to demonstrate and optimize the utility of the system. Using patient-derived induced pluripotent stem cells differentiated into neurons as a model system, RNA mis-splicing diseases will be targeted as a proof-of-concept to modulate alternative splicing. This proposal expects to enable a robust, flexible platform to interrogate gene expression, study transcript dynamics, and dissect the function of coding and noncoding transcripts.